Genetic factors behind Zika scourge revealed

For a disease newly-established in popular consciousness through a rash of newspaper headlines by turns plaintive or horrifying, there are hopeful reasons to believe that in epidemiological terms, the reign of the Zika virus will be short-lived and its range limited.

New research shows that, contrary to early assumptions that vulnerability to Zika was linked to poverty and environment and so could quickly spread across the world’s under-developed regions, the reasons for the most horrifying manifestations of the disease in infants seem to be genetic in origin.

There’s no doubt the Zika virus has the potential to cause large numbers of babies to be born with abnormally small heads and brain damage (a condition termed microcephaly) as well as epilepsy, skeletal alterations, auditory and visual handicaps. Yet not every unborn infant goes on to show these symptoms if the mother gets the disease. In fact it is observed in only 6%-12% of cases.

Scientists now suspect that congenital Zika syndrome (CNZ), not the infection itself, defines the seriousness of response. A new study published on February 2 in the journal Nature Communications offers strong evidence that the higher susceptibility of some babies to the virus has a genetic origin.

The study’s Brazilian authors researched 91 babies born to infected mothers, and came up with some startling findings about genetically-based resistance. For example, they found that while identical twins were likely to have the same vulnerability to microcephalic defects, non-identical twins had different levels of resistance.

Comparative images of  microcephaly effect on infants. Image courtesy of  CDC

Comparative images of microcephaly effect on infants. Image courtesy of CDC

This virus burst upon the world in the run-up to the 2016 Rio Olympics, providing the justification for some athletes to stay away. It also sent shock-waves through regions populated by Aedes Egyptii, the mosquito responsible for spreading dengue fever, chikungunya, yellow fever virus, as well as Zika.

A recent article in the London Guardian profiling poor families in northern Brazil carrying the burden of this disease, encapsulates the collective anxiety and pathos that Zika generates. The article profiles a handful of the estimated 3,037 infants in Brazil affected by the outbreak that threatened to sweep across the Americas prompting the World Health Organization to declare Zika a public health emergency across 23 countries.

In the United States, the Center for Disease Control (CDC) reported that across the continental USA 2,395 pregnant women had exhibited Zika-like symptoms up to January 2018, with a total of 106 infants showing Zika birth defects.

One hotspot in Brazil is Recife, the capital or Pernambuco state where 438 microcephalic children were born around two years ago. The Guardian article profiles harrowing cases of families affected by the diseases, and the efforts of community-based groups such as the Union of Mothers of Angels to bring relief.

Spurred by popular concern, scientists got to work unravelling Zika and the way it affects different populations differently, in hopes of rapidly creating a vaccine. Already, the first assessments coming in: a comparative study of two new potential DNA vaccines expressing Zika virus structural proteins was published  in The Lancet  December 2017.

Brazil’s own genetic study, whose principal investigator is Mayana Zatz, a professor at the University of São Paulo’s Bioscience Institute (IB-USP), focuses on neural progenitor cells (NPCs) the type most affected by Zika in the developing infant brain.

Most of the investigation was conducted at the Human Genome and Stem-Cell Research Center (HUG-CELL), one of the Research, Innovation and Dissemination Centres (RIDCs) supported by FAPESP. HUG-CELL is hosted by the University of São Paulo (USP).

The first phase of research involved the study of twins — both identical and non-identical — born during the 2015-2016 Zika outbreak. 91 babies born to infected mothers were located, including two pairs of identical (monozygotic) twins and seven pairs of non-identical (dizygotic twins).

Inspired by the induced pluripotent stem cell (iPSC) technique for which Shinya Yamanaka, of Japan’s University of Kyoto won the 2012 Nobel Prize in Medicine, the HUG-CELL team developed a method to convert sampled blood from these infected infants into iPSCs, which like embryonic stem cells can differentiate into almost any type of human cell or tissue.

The next step was to convert the iPSCs into neural progenitor cells (NPCs), the type most affected by Zika in the developing infant brain. As soon as the NPCs from the affected babies and their unaffected siblings were established in vitro, all cultures were infected with a Brazilian strain of Zika virus.

Zika's  cycle of infection. Infographic  from CDC

Zika’s cycle of infection. Infographic from CDC

“From the start, we were struck by the fact that the virus replicated much faster in the NPCs from the affected babies,” Prof. Zatz told a Brazilian journalist. “In addition, these cells proliferated less and died more than cells from unaffected babies. We appeared to have succeeded in reproducing in vitro what happens in vivo.”

Next, in collaboration with a team of researchers led by Sergio Verjovski-Almeida at IQ-USP, the scientists used sequencing techniques to analyse all the messenger RNA molecules expressed by the cultured NPCs.

Their study of the non-identical twins showed cases where only one twin was affected by the virus despite both having been exposed to the virus during pregnancy. The researchers found some 60 genes with differentiated expression in the neural progenitor cells of the affected babies.

Differences were observed in two cell signalling pathways of key significance for brain development during the embryonic period – one mediated by the protein mTOR and the other by Wnt.

“These pathways regulate the proliferation and migration of central nervous system cells, among other things,” Prof. Zatz said. “The expression of several genes linked to these pathways was reduced in the NPCs from affected babies. One was 12.6 times less expressed in affected cells than the same gene in cells from the unaffected twin.”

The results were similar for all three pairs of twins studied, reinforcing the hypothesis that congenital Zika syndrome  (CNZ) is not a random event but is favoured by genetic factors.

Aedes Aegyptii mosquito  responsible for a trio of infectious diseases

Aedes Aegyptii mosquito responsible for Zika plus a trio of infectious diseases

Nevertheless genetic susceptibility to Zika is a complex inheritance, not dissimilar to diabetes. It is not the case that genetic variants are present only in affected babies, but rather that vulnerability results from a combination of differentially expressed genes.

In the case of congenital Zika syndrome, viral infection may be the environmental factor that triggers the development of the disease. In time, perhaps, parents will know in advance what the risk levels are of having children with this more vulnerable genetic profile. And this of course will help both to develop a vaccine, and to identify priority targets for vaccination. Perhaps, in  future, parents carrying certain genes  and living in  Zika-prone areas may be encouraged to hold off having children, as is the case with sickle cell anaemia gene carriers in Saudi Arabia.

Other participants in the Brazilian study described in the Nature article were: the National Energy & Materials Research Centre (CNPEM), the Federal University of São Paulo (UNIFESP), Butantan Institute, the Albert Einstein Jewish Hospital (HIAE) in São Paulo, USP’s Chemistry Institute, and the Federal Universities of Paraíba (UFPB), Rio Grande do Norte (UFRN) and Pernambuco (UFPE). Data collection was performed in 2016, mainly in states of the Northeast affected by the Zika epidemic in the previous year.

Research into genetic resistance to the disease within the human organism is just one battlefront in the war against Zika: another is to attack the mosquito vector. In the USA, CDC reports the presence of Zika-bearing mosquitoes in Texas and Florida. In Miami, Florida, health officials are investing in a project to release millions of Aedes Egyptii mosquitoes infected with Wolbachia, a bacteria that only affects the insects and renders the males sterile.

You can read the Nature Communications article by clicking here.

You can read an article by Brazilian journalist Karina Toledo by clicking here.

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